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- PDB-8wcc: Cryo-EM structure of the CHA-bound mTAAR1 complex -

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Basic information

Entry
Database: PDB / ID: 8wcc
TitleCryo-EM structure of the CHA-bound mTAAR1 complex
ComponentsTrace amine-associated receptor 1
KeywordsMEMBRANE PROTEIN / CHA / mTAAR1
Function / homology
Function and homology information


G protein-coupled amine receptor activity / Amine ligand-binding receptors / trace-amine receptor activity / G alpha (s) signalling events / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G protein-coupled receptor signaling pathway / endoplasmic reticulum membrane ...G protein-coupled amine receptor activity / Amine ligand-binding receptors / trace-amine receptor activity / G alpha (s) signalling events / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G protein-coupled receptor signaling pathway / endoplasmic reticulum membrane / membrane / plasma membrane
Similarity search - Function
Trace amine associated receptor 1 / Trace amine associated receptor family / : / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
CYCLOHEXYLAMMONIUM ION / Trace amine-associated receptor 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.04 Å
AuthorsRong, N.K. / Guo, L.L. / Zhang, M.H. / Li, Q. / Yang, F. / Sun, J.P.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81773704 China
CitationJournal: Cell / Year: 2023
Title: Structural and signaling mechanisms of TAAR1 enabled preferential agonist design.
Authors: Pan Shang / Naikang Rong / Jing-Jing Jiang / Jie Cheng / Ming-Hui Zhang / Dongwei Kang / Lei Qi / Lulu Guo / Gong-Ming Yang / Qun Liu / Zhenzhen Zhou / Xiao-Bing Li / Kong-Kai Zhu / Qing- ...Authors: Pan Shang / Naikang Rong / Jing-Jing Jiang / Jie Cheng / Ming-Hui Zhang / Dongwei Kang / Lei Qi / Lulu Guo / Gong-Ming Yang / Qun Liu / Zhenzhen Zhou / Xiao-Bing Li / Kong-Kai Zhu / Qing-Biao Meng / Xiang Han / Wenqi Yan / Yalei Kong / Lejin Yang / Xiaohui Wang / Dapeng Lei / Xin Feng / Xinyong Liu / Xiao Yu / Yue Wang / Qian Li / Zhen-Hua Shao / Fan Yang / Jin-Peng Sun /
Abstract: Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment ...Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.
History
DepositionSep 11, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 27, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Trace amine-associated receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7572
Polymers37,6571
Non-polymers1001
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Trace amine-associated receptor 1 / TaR-1 / Trace amine receptor 1


Mass: 37656.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Taar1, Ta1, Tar1, Trar1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q923Y8
#2: Chemical ChemComp-HAI / CYCLOHEXYLAMMONIUM ION


Mass: 100.182 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14N / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of the CHA-bound mTAAR1 complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 1.875 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 296951 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0312143
ELECTRON MICROSCOPYf_angle_d2.9032920
ELECTRON MICROSCOPYf_dihedral_angle_d11.736292
ELECTRON MICROSCOPYf_chiral_restr0.104345
ELECTRON MICROSCOPYf_plane_restr0.02348

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